Use of mTOR Inhibition among Candidates on Waiting List for Lung Transplantation: Is it Time for Consensus?

Inhibitors of the mammalian target for rapamycin (mTOR) - the two agents being sirolimus and everolimus - are commonly used as immunosuppressants in solid organ transplant. These agents are used in lung transplantation for a variety of reasons: to augment standard immunosuppression; to allow for lower levels of calcineurin inhibitors (as in the case of renal dysfunction); to protect against malignancies (especially skin malignancies); or as a means of stabilizing chronic lung allograft dysfunction (CLAD).

Two single-center trials looked at the use of sirolimus de novo at the time of transplantation (in place of azathioprine) as part of the initial immunosuppression regimen, starting at the time of transplant [1,2]. In both of these trials, an increased rate of bronchial anastomosis dehiscence was observed and patient deaths ensued. These observations resulted in a "black box warning" on drug labels for these products. Indeed, wound healing problems are recognized in heart transplant patients who take these drugs and have various types of surgical procedures [3,4].

More recently, the drug sirolimus has been shown to slow the decline in lung function in patients with the rare lung disease lymphangioleiomyomatosis (LAM) [5]. Use of the drug can stabilize these patients for extended periods of time and has impressive efficacy in controlling chylous effusion production [6] and renal angiomyolipoma and abdominal lymphangiomyoma tumor growth [7]. In other words, these drugs have become an important part of the chronic care of patients with LAM, many of whom go on to need lung transplantation if lung disease worsens.

Sirolimus has a serum half-life of about 60 hours, meaning that the drug may remain active in a patient for nearly two weeks. Everolimus has a much shorter serum half-life, at 30 hours, which still means about 7 days before the drug has been eliminated once it is stopped.

Given that the indication/need for mTOR inhibition in the setting of CLAD is not imperative and the concern around bronchial anastomosis dehiscence, and with the uncertainty in timing of the retransplant, a common practice is to stop these drugs in a patient with chronic rejection who is listed for redo lung transplant.

But given that there is a much stronger clinical imperative to use mTOR inhibition in LAM patients with severe disease, does this same approach make sense? The benefits realized by staying on the drug during a wait on the transplant list (often for many months) may outweigh the concerns around their use going into the transplant. For one thing, the tragic outcomes seen with the use of sirolimus in the two sentinel studies involved their use ongoing from the time of transplant. In the case of LAM patients awaiting transplant, they would stop the drug at the time of transplant and have diminishing levels after the operation. Also, the use of everolimus (with the shorter terminal half-life) rather than sirolimus can offer a quicker elimination of the drug from the recipient.

In the end, it boils down to a case of weighted benefits and risk. Does the risk of not using and mTOR inhibitor in a patient with severe LAM awaiting transplant (more rapid decline in lung function, uncontrolled chylous effusions, more oxygen need, more dyspnea, a possibility of not living long enough to find a donor) outweigh a risk associated with bronchial healing problems -- in a scenario different from what was observed in the two clinical trials of concern? A study looking at everolimus use up until the time of transplant in treating idiopathic pulmonary fibrosis did not demonstrate an increased use of anastomotic dehiscence in those patients who had lung transplants during therapy [8] (albeit with a small "n").

While some lung transplant programs are allowing for continued use of an mTOR inhibitor (often everolimus due to the quicker elimination) while awaiting transplant, many others prohibit their use. In some countries, the allocation system allows for a program to prioritize a patient for transplant in just this situation and minimize wait time "off the mTOR inhibitor". There are not ample data to drive decision making in this situation; a risk/benefit analysis should be undertaken at each individual program in this regard. Many are calling for allowance of continued use of the drugs for LAM patients awaiting lung transplantion [9]. ■

Disclosure Statement: The author has no conflicts of interest to disclose.